Glucocorticoids are implicated as causative factors in age-related cognitive decline. Prior and preliminary data support a central hypothesis that aged, cognitively impaired Long-Evans rats (AI) exhibit more potent (GR) mediated transcription of hippocampal genes associated with neuronal dysfunction or degeneration than young (Y) or aged unimpaired (AU) rats. Specific aims will use unchallenged rats and rats with elevated circulating glucocorticoid induced by stress, corticosterone or dexamethasone administration. Wild type mice and NF-kappaB-p50 null mice will serve as useful controls in aims 2 and 3. Hippocampal glucocorticoid receptor transcription complexes will be characterized and quantified by electromobility gel shift, western immunoblot and co- immunoprecipitation assays. Gene expression profiles will be assessed using Genechip microarrays. Aim #1: will test the hypothesis that AI rats exhibit elevated GR mediated transcription and have higher levels of active GR relate to MR. Aim #2: will test the hypothesis that AI rats exhibit reduced association of NF-kappaB (NF-kappaB) with GR and develop approaches to functionally inhibit GR: NF-kappaB interaction. Aim #3 will test if cholinergic input from the basal forebrain regulates levels of GR, MR, GRE binding activity or composition. Findings from gene microarray experiments are relevant to all sub- projects of the PPG but this project has particular interactions with and relevance to sub-projects #2 and #4.